In Vivo Structure-Function Studies on the Precise Role of ErbB-2 Signaling in Mammary Gland Development
Annual rept. 1 Sep 2001-1 Sep 2002
MCMASTER UNIV HAMILTON (ONTARIO)
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The ErbB-2Neu receptor tyrosine kinase plays important roles in development and disease. To genetically dissect the ErbB-2 mediated signaling pathway in vivo, we have generated neu cDNA knock-in mutants harboring subtle mutations and expressed under the transcriptional control of the endogenous promoter. We have shown that the kinase activity of ErbB-2 is essential for embryonic development since this mutant is a phenocopy of the erbB-2 null mutants. We also demonstrate that the loss of tyrosine 1028 results in a hypermorphic phenotype in animals, strongly suggesting that Y1028 does indeed convey a negative regulatory signal on ErbB-2. The mechanism for this action is under investigation. However, we investigated the possibility that c-Cbl was mediating this downregulatory action by interacting with YlO2B and targeting ErbB-2 for ubiquitylation and degradation. Although we did not observe c-Cbl association with Y1028, we did identify c-Cbl association with two other tyrosine phosphorylation sites, Y1144 and Yl227. The nature and significance of this interaction is currently under investigation. The identity of signaling events that may lead to the downregulation of ErbB-2 would have important therapeutic and clinical implications.
- Anatomy and Physiology
- Medicine and Medical Research